PB2026: ROLE OF MOLECULAR PROFILING IN MYELODYSPLASTIC SYNDROME IN REAL-WORLD - A NEW APPROACH IN MYELODYSPLASTIC SYNDROME’S RISK STRATIFICATION?
Authors: Duarte Pacheco Silva, Pedro Pinho Moura, Cátia Raquel Almeida Pais, Bárbara Marques, João Gaião Santos, Ana Teresa Simões, Ana Catarina Oliveira, Margarida Coucelo, Emília Cortesão
Journal: HemaSphere (2023)

Topic: 10. Myelodysplastic syndromes - Clinical Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of neoplasms, characterized by somatic mutations in genes involved in DNA methylation, chromatin modification, signal transduction, among others. Risk stratification and therapeutic decision-making of MDS are based on the International Prognostic Scoring System-Revised (IPSS-R), which considers hematologic parameters and cytogenetic abnormalities, and more recently, a Molecular International Prognostic Scoring System (IPSS-M), developed by Richard et al, also takes mutations in 31 genes in account. Aims: We aim to evaluate the mutation profiling in MDS and investigate the IPSS-M in daily clinical practice. Methods: Single-center retrospective study of 48 patients diagnosed with MDS with molecular characterization with a next generation sequencing (NGS) Custom Myeloid Panel performed in pretreatment diagnostic or peridiagnostic samples. Hematologic parameters, risk stratification and cytogenetic abnormalities were collected, and prognosis of IPSS-M risk groups (Leukemia free survival, LFS, and overall survival, OS), comparing with previous IPSS-R. Results: Patients median age was 67 (25-86) years, being 25 (52.1%) males. Anemia (Hb <10g/dL, n=23, 47.9%) and thrombocytopenia (Platelets < 100, n=23, 47.9%) were the most common cytopenias and 22 patients (45.8%) had 2 or more cytopenias. The cytogenetics were good in most patients (37, 77.2%), and 39.6% (19) had ≤2% medullary blasts. At least one mutation was found in 70.8% of patients (34) and 27.1% (13) patients had at least 3 mutations. The later presented a worse prognosis evaluated by LFS (HR 3.4(1.4-8.0), P=0.007) and OS (HR 3.4(1.4-8.0), P=0.007). Most common mutations were TET2, ASXL1, SF3B1, DNMT3A and JAK2, accounting for 25.0%, 25.0%, 22.9%, 14.6% and 12.5%, respectively. Mutations in TP53 (HR 9.5[1.1-84.1], P=0.042), were significantly associated with adverse outcome in OS, but only CBL were statistically predictor of LFS (HR 213.1[4.3-10535.7], P=0.007). According to the IPSS-R categories, most of patients were low risk (n=17, 35.4%) or very high risk (n=6, 12.5%). Applying the IPSS-M, 18 (37.5%) patients were low risk, 9 (18.8%) high risk and 13 (27.1%) very high risk. The OS was significantly different between groups in IPSS-R and IPSS-M. The median OS per IPSS-R score was NA, NA, 59.4, 24.1, 11.6 months for very low-, low-, intermediate-, high-, and very high-risk, respectively, P<0.001. In IPSS-M score, the median OS was NA, 116.5, 59.4, 20.5, 25.8 and 9.4 months for very low-, low-, mod low, mod high, high-, and very high-risk, respectively, P<0.001. The prediction ability of prognosis by IPSS-R and IPSS-M was assessed by the area under the curve (AUC) of ROC with OS in R, being higher in IPSS-M (0.605 vs 0.581). We evaluate the clinical significance of the IPSS-M, comparing the risk stratifications changes after merge moderate low and moderate high into moderate. Twenty one (43.8%) patients were reclassified, 10 (20.8%) were upstage and 11 (22.9%) downstage. After reclassification according IPSS-M, 4 (8.3%) patients would benefit from disease-modifying strategies. Summary/Conclusion: Most patients had at least one mutation and the number of abnormalities, as well as mutations in TP53 and CBL, were correlated with disease severity and outcome. IPSS-M, integrating hematologic and cytogenetic parameters with gene mutations, improved the risk stratification of patients with MDS, representing a valuable tool for clinical decision making and patient-centered approach. Keywords: Risk factor, Gene mutation, Myelodysplastic syndrome, Mutation